Practice Essentials

Approximately 30-50% of colorectal tumors are known to have a mutated (abnormal) KRAS gene, indicating that up to 50% of patients with colorectal cancer (CRC) might respond to anti-epidermal growth factor receptor (EGFR) antibody therapy. However, 40-60% of patients with wild-type KRAS tumors do not respond to such therapy.
[1] In these patients, data suggest that the mutated BRAF gene, which is present in 5-10% of tumors, can affect response to these agents.
[2, 3, 4]

Clinical implications of KRAS/BRAF

Patients with mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy; it remains unclear that patients with KRAS wild-type CRC will definitely respond, although these individuals may be able to derive some benefit from anti-EGFR therapy. Patients with metastatic CRC who are being considered for anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to therapy.

It is unclear to what extent the lack of response in KRAS wild-type CRC is due to BRAF mutations, but data suggest that mutated BRAF confers resistance to anti-EGFR therapy given beyond first-line treatment.
[5, 6]

Additionally, testing for microsatellite instability and mismatch repair lends information for the option to use pembrolizumab, a PD-1 inhibitor. Pembrolizumab gained accelerated approval from the FDA in May 2017 for unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. It is also approved for any solid tumor that has tested positive for MSI-H or MMR deficiency in patients who have had prior treatment and have no satisfactory alternative treatment options.
[12]

Laboratory testing for KRAS/BRAF

Lab tests include the following:

The therascreen KRAS RGQ (Rotor-Gene Q) PCR (polymerase chain reaction) Kit. Tests for mutations in codons 12 or 13 of the KRAS gene on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis. PCR amplification and DNA sequence analysis or allele-specific PCR for BRAF V600E mutation status on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis.

Overview

One actively investigated approach in the management of advanced and metastatic colorectal cancer (CRC) has been the delivery of agents whose primary purpose is to interfere with the biological activity of the epidermal growth factor receptor (EGFR).

However, it is well-recognized that only a subset of patients whose colorectal tumors have been demonstrated to over express the EGFR receptor on their cell surfaces will actually exhibit a favorable biological and clinical response to anti-EGFR antibody therapy. Both the costs and potential toxicities associated with this management paradigm add to the relevance of efforts to more critically define particular patient populations that would be most likely to respond to treatment with this class of agents, or, conversely, that would be highly unlikely to exhibit clinical benefit.

Randomized trials in patients with metastatic CRC that included anti-EGFR antibody therapy have specifically evaluated the impact of the mutational status of KRAS (wild-type [normal] versus mutated [abnormal]) on patient outcome. Notably, the presence of a KRAS mutation was found to be associated with the absence of biological and clinical activity for the anti-EGFR antibody treatment.
[7, 8, 14]

Approximately 30% to 50% of colorectal tumors are known to have a mutated (abnormal) KRAS, indicating that up to 50% of patients with CRC might respond to anti-EGFR antibody therapy. However, 40% to 60% of patients with wild-type KRAS tumors do not respond.
[1] In these patients, data suggest that mutated BRAF, which is present in 5% to 10% of tumors, can affect response to these agents.
[5, 6, 10]

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Clinical Implications of the Genetic Mutations

Several phase II/III randomized trials have revealed the favorable impact on survival associated with the administration of one of two currently available anti-EGFR antibodies (cetuximab [Erbitux], panitumumab [Vectibix]) in patients with KRAS wild-type.
[7, 8, 9, 10] In July 2012, the indication for cetuximab was updated to specify treatment of KRAS mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer as determine by FDA-approved tests (eg, therascreen KRAS RGQ PCR Kit).

A careful read of the data from these and other trials clearly demonstrates that patients with mutated KRAS are unlikely to benefit from anti-EGFR antibody therapy. However, it is not clear that patients with KRAS wild-type will definitely respond, only that they have a reasonable opportunity to derive clinical benefit from the therapy. For example, in the panitumumab vs best supportive care trial, there were no responders in the mutated KRAS group randomized to the therapy and only a 17% partial response rate was noted in the KRAS wild-type group.
[8]

It is unclear to what extent the lack of response in KRAS wild-type patients is due to BRAF mutations, but current data suggest that mutated BRAF confers resistance to anti-EGFR therapy given beyond first-line treatment. A retrospective analysis of 113 patients who received cetuximab or panitumumab demonstrated that none of the KRAS wild-type patients with BRAF mutations responded to therapy, and that none of the responders had BRAF mutations. In addition, BRAF mutant patients showed prolonged progression-free and overall survival compared with BRAF wild-type patients.
[5] Similarly, a retrospective pooled analysis of the two phase III cetuximab studies demonstrated that the best treatment outcomes were observed in patients with both KRAS wild-type and BRAF wild-type tumors, but there were too few patients with BRAF mutations to determine whether BRAF mutation status alone could predict response to therapy.
[6]

Finally, in the cetuximab plus FOLFIRI study, although mutated BRAF was associated with a poor prognosis, it did not independently predict response to treatment.
[10] Thus, although results from these and other studies are compelling, there are as yet no prospective data that can definitively determine the role of BRAF status in response to EGFR inhibitor therapy.

Based on these observations, it is vital that patients with metastatic CRC who are being considered for treatment with anti-EGFR antibody therapy should be tested for the presence of a KRAS mutation prior to the administration of therapy and that both cetuximab and panitumumab be initiated only in patients with KRAS wild-type. This will ensure that the therapy is not administered to patients who are unlikely to obtain benefit.
[17, 18] In fact, NCCN Clinical Practice Guidelines recommend testing for KRAS mutations at the time of diagnosis of stage IV disease so as to better prepare an appropriate management plan in case treatment with an anti-EGFR antibody is later considered.
[17] Cetuximab labeling specifies use in CRC KRAS wild-type tumors and panitumumab labeling states use is not recommended for treatment with KRAS mutations. BRAF mutation status should be determined only after KRAS wild-type is detected.
[17]

Testing for microsatellite instability and mismatch repair lends information for the option to use pembrolizumab for unresectable or metastatic colon cancer that has tested positive for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) and has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
[12]

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Testing for the Genetic Mutations

Testing for mutations in codons 12 or 13 of the KRAS gene can be performed on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis using a variety of methods. BRAF V600E mutation status is determined via PCR amplification and DNA sequence analysis or allele-specific PCR on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis.

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Genentech; Astra-Zeneca ; Clovis; Tesaro<br/>Received income in an amount equal to or greater than $250 from: Astra-Zeneca; Clovis; Genentech; Tesaro; Celgene<br/>Received consulting fee from Genentech; Received consulting fee from Cellgene; Received consulting fee from Crititech; Received consulting fee from Amgen.